Xylose (xylopyranose):H+ symporter of 491 aas and 12 TMSs (Wambo et al. 2017). Also transports and binds D-glucose and 6-bromo-6-deoxy-D-glucose. The 3-d structure is known in three conformers, outward occluded, inward occluded and inward open (Sun et al. 2012: Quistgaard et al. 2013). Most of the sugar-binding residues are conserved with the human Glut-1, 2, 3 and 4 homologues. The coalescence of intramolecular tunnels and cavities has been postulated to account for facilitated diffusion of sugars (Quistgaard et al. 2013). Most of the sugar-binding residues are conserved with the human Glut-1, 2, 3 and 4 homologues. The coalescence of intramolecular tunnels and cavities has been postulated to account for facilitated diffusion of sugars (Cunningham and Naftalin 2014).

Glucose uniporter, Glut3 (also transports dehydro-ascorbate; Maulén et al., 2003). Down-regulated in the brains of Alzheimer's disease patients (Liu et al., 2008b). The structure of the human orthologue with D-glucose bound was solved at 1.5 Å resolution in the outward occluded conformation (Deng et al. 2015). Sugars are predominantly coordinated by polar
residues in the C-terminal domain. The conformational transition from the outward-open to the outward-occluded states entails a prominent local rearrangement of the extracellular part of
TMS 7. Comparison of the outward-facing GLUT3 structures with inward-open GLUT1 provides insight
into the alternating access cycle for GLUTs, whereby the C-terminal domain provides the primary
substrate-binding site and the N-terminal domain undergoes rigid-body rotation with respect to
the C-terminal domain (Deng et al. 2015).

Fructose uniporter, GLUT5. The proteins from rat and cow have been crystalized and their structures have been determined in the open outward- and open inward-facing conformations, respectively. On the basis of comparisons of
the inward-facing structures of GLUT5 and human GLUT1, a ubiquitous glucose transporter, a single point mutation proved to be enough to switch the substrate-binding preference from
fructose to glucose. A comparison of the substrate-free structures of GLUT5 with occluded substrate-bound structures of E. coli XylE suggested that, in addition to a global rocker-switch-like
re-orientation of the bundles, local asymmetric rearrangements of carboxy-terminal transmembrane
bundle helices, TM7 and TM10, underlie a 'gated-pore' transport mechanism (Nomura et al. 2015). GLUT5 is preferentially used for fructose uptake under (near) anoxic glycolysis to avoid feedback inhibition of phosphofructokinase (Park et al. 2017). Residues involved in fructose recognition have been identified (Ebert et al. 2017).

Hexose:H+ symporter of 534 aas and 12 TMSs. Substrate
accumulation can be up to 1500-fold; one proton is symporter per
hexose taken up. Helices I, V, VII and XI interact with the sugar during
translocation
and line the transport path through the membrane (Tanner 2000).

Glucose/mannose/fructose transporter and high affinity sensor, Snf3p (regulates glucose transport via other systems). Residues involved in ligand preference are similar to those involved in transport (Dietvorst et al. 2010). Snf3p in Candida glabrata is essential for growth in low glucose media but not high glucose media, and plays a role in the induction of severall hexose transporters (Ng et al. 2015).

Glucose transporter and low affinity sensor, Rgt2p (regulates glucose transport in conjunction with Snf3p). Rgt2 generates an intracellular signal in response to glucose that leads to inhibition of the Rgt1 transcriptional repressor and consequently to derepression of HXT genes encoding glucose transporters. They have unusually long C-terminal tails that bind to Mth1 and Std1, paralogous proteins that regulate the function of the Rgt1 transcription factor. Scharff-Poulsen et al. 2018 showed that the C-terminal tail of Rgt2 is not responsible for its inability to transport glucose. RGT2 mutations that cause constitutive signal generation alter evolutionarily-conserved amino acids in the transmembrane spanning regions involved in maintaining an outward-facing conformation or the substrate binding site. These mutations may cause Rgt2 to adopt inward-facing or occluded conformations that generate the glucose signal.

Hexose (Glucose and Fructose) transporter, PfHT1 of 504 aas and 12 TMSs. This is the only hexose transporter, and it is found in the plasma membrane. It is an antimalarial drug target (Meier et al. 2018).

Myoinositol:H+ symporter, HMIT (also transport other inositols including scyllo-, muco- and chiro-, but not allo-inositol) (Aouameur et al., 2007). Expressed in the Golgi of the hippocampus and cortex. May also transport inositoltriphosphate (Di Daniel et al., 2009). Interacts directly with γ-secretase (9.B.47.1.1) to regulate its activity and the production of Abeta production, important in Alzheimer's disease (Teranishi et al. 2015).

The glucose/fructose:H+ symporter, STP13 (sugar transport protein 13). Expressed in vascular tissues and induced during programmed cell death (Norholm et al., 2006). Used to combat bacterial infection by competing with them for sugars by phosphorylation of STP13 by the BAK1 receptor kinase (Yamada et al. 2016).

The glucose transporter, GLUT10, was originally believed to be responsible for Type 2 diabetes. It is now believed to be responsible for arterial tortuosity, a rare autosomal recessive connective tissue disease (Callewaert et al., 2007). GLUT10 transports glucose and 2-deoxy glucose (Km=0.3 mM), and is inhibited by galactose and phloretin (Coucke et al., 2006).

The fructose/xylose:H+ symporter, PMT1 (polyol monosaccharide transporter-1). Also transports other substrates at lower rates. PMT2 is largely of the same sequence and function. Both are present in pollen and young xylem cells (Klepek et al., 2005). A similar ortholog has been identifed in pollen grains of Petunia hybrida (Garrido et al. 2006).

Glucose transporter, GT1. GT1, 2, and 3 are homologues. GT2 and GT3 transport ribose as well as glucose at different rates. GT3 transports ribose with 6-fold lower efficiency due to two threonines in GT3 that are alanines in GT2. They are in two loops between TMSs 3, 4, and 7, 8 (Naula et al., 2010). GT1 is expressed in the flagellar membrane and may be both a glucose transporter and sensor, allowing the parasites to enter the
stationary phase when they deplete glucose although in the absence of
the sensor, they lose viability (Rodriguez-Contreras et al. 2015).

solute carrier family 2, member 12, Glut12 of 617 aas and 12 TMSs. In contrast to most mammalian members of this family, this protein has been reported to be a glucose:proton symporter (Wilson-O'Brien et al. 2010).

Glucose transporter Rco-3 or MoST1. MoST1 plays a
specific role in conidiation and mycelial melanization which is not
shared by other hexose transporter family members in M. oryzae (Saitoh et al. 2013).

Sorbitol (glucitol):H+ co-transporter, SOT2 (Km for sorbitol of 0.81 mM) of 491 aas and 12 TMSs (Gao et al. 2003). SOT2 of Prunus cerasus is mainly expressed only
early in fruit development and not in leaves (Gao et al. 2003).

Glycerol:H+ symporter of 530 aas and 12 TMSs, GT1. It is essnetial for the glycerol repression of the alcohol oxidase 1 (AOX1 gene (Zhan et al. 2016), and plays a role in glycerol and methanol metabolism in Pichia pastoris (Li et al. 2017).

Myo inositol uptake porter of 574 aas and 12 TMSs, Fst1. Also takes up the polyketide mycotoxin produced by Fusarium verticillioides during the
colonization of maize kernels, Fumonisin B1 (FB1). The activity was demonstrated with the orthologue in Weissella verticillioides (Niu et al. 2016).

Glucose transporter 1, GLUT1 or Slc2A1 of 491 aas and 12 TMSs. Expression occurs in the mesodermal region of Xenopus embryos, especially in the dorsal
blastopore lip at the gastrula stage. It is an important player
during gastrulation cell movement (Suzawa et al. 2007).

Chromaffin granule monoamine (and drug) transporter, VAT1. It is involved in the transport of biogenic
monoamines such as serotonin from the cytoplasm into the secretory
vesicles of neuroendocrine and endocrine cells (Essand et al. 2005). It is strongly inhibited by reserpine, and to a lesser extent by ketanserin and fenfluramine, but not by tetrabenazine (Erickson et al. 1996).

The vesicular acetylcholine transporter, VAChT (pumps acetylcholine into synaptic vesicles). The acetyl choline and vesamicol binding sites are near the luminal end of the transport pathway (Khare et al. 2010).

The multidrug resistance protein Aqr1 (YNL065w) (exports short chain monocarboxylates but not more hydrophobic acids such as octonate and quinidine. Also exports ketoconazole and crystal violet (Tenreiro et al., 2002)).

The multidrug efflux pump, Qdr3 (exports polyamines, quinidine, barban, cisplatin and bleomycin). The two halves of the protein each have an N-terminal. 150 residue hydrophilic region found in many fungi followed by a 200 residue, 6 TMS, transmembrane region. This suggests that an intragenic duplication event gave rise to 12 TMS proteins independently of most other MFS carriers, but this has not been demonstrated, possibly because of extensive sequence divergence of the second half.

NCL7 or MFSD8. Neuronal ceroid lipofuscinosis, NCL, a neuro-degenerative genetic disease, is caused by mutations in at least 8 different human genes, one of which, CLN7 (MFSD8), is associated with late infantile NCL. CLN7 is localized to lysosomes (Sharifi et al., 2010). Loss of this putative lysosomal transporter in the brain leads to lysosomal dysfunction, impaired constitutive autophagy and neurodegeneration late in the disease (Brandenstein et al. 2015).

YajR of 454 aas and 12 TMSs. The 3-D structure in the outward-facing conformation is available at 3.15Å resolution, and the cytoplasmic C-terminal YAM domain has been solved to 1.07Å resolution. This 65 aa YAM domain is thought to control the conformational states of the protein (Jiang et al. 2013; Jiang et al. 2014).

SPX domain-containing membrane protein At1g63010, called VacuolarPhosphate Transporter 1 (VPT1), It transports phosphate > sulphate > nitrate > chloride and malate. The vpt1 mutant plants were stunted and consistently
retained less Pi than wild type plants, especially when grown in medium
containing high levels of Pi. In seedlings, VPT1 was expressed primarily
in younger tissues under normal conditions, but was strongly induced by
high-Pi conditions in older tissues, suggesting that VPT1 functions in
Pi storage in young tissues and in detoxification of high Pi in older
tissues. As a result, disruption of VPT1 rendered plants hypersensitive
to both low-Pi and high-Pi conditions, reducing the adaptability of
plants to changing Pi availability (Liu et al. 2015).

The CefM
protein of 482 aas and 12 TMSs. Probably involved in the translocation of penicillin N from the lumen of peroxisomes (or
peroxisome-like microbodies) to the cytosol, where it is converted into cephalosporin C (Teijeira et al. 2009). A null mutant
accumulates penicillin N, is unable to synthesize deacetoxy- and deacetyl-cephalosporin C as well as cephalosporin C, and shows impaired differentiation into arthrospores (Teijeira et al. 2009).

ZIF2 (Zinc-Induced Facilitator 2) of 484 aas and 12 TMSs localises primarily at the tonoplast of root cortical cells and is a functional transporter able to mediate Zn efflux from the cytoplasm (Remy et al. 2014). Activity is controlled by alternative RNA splicing.

TetA class C (TetA(C)) of 396 aas and 12 TMSs. The TetA(C) of the transposon, Tn10, not only exports tetracycline by a proton antiport mechanism, it also increases susceptibility to cadmium, fusaric acid, bleomycin and several classes of cationic aminoglycoside antibiotics (Griffith et al. 1995). For this reason, it has been used to generate dual counter selection procedures (Li et al. 2013). It is not certain that this is due to import of these compounds as this increased susceptibility could be due to a secondary effect.

MFS carrier of 490 aas and 12 TMSs, MfsD14a or Hiat1 (Hippocampus abundant transcript 1 protein). 76% identical to 2.A.1.2.30. Mutant mice (Mus musculus, strain 129S6Sv/Ev) were generated with the Mfsd14a gene disrupted with a LacZ reporter gene. Mutant mice are viable and healthy, but males are sterile due to a 100-fold reduction in the number of spermatozoa in the vas deferens. Male mice have adequate levels of testosterone and show normal copulatory behaviour. The few spermatozoa that are formed show rounded head defects similar to those found in humans with globozoospermia. Spermatogenesis proceeds normally up to the round spermatid stage, but the subsequent structural changes associated with spermiogenesis are severely disrupted with failure of acrosome formation, sperm head condensation and mitochondrial localization to the mid-piece of the sperm. Mfsd14a expression occurs in Sertoli cells, suggesting that MFSD14A may transport a solute from the bloodstream that is required for spermiogenesis (Doran et al. 2016).

ThMFS1 of 563 aas and 14 TMSs. Catalyzes export of fungicides causing tolerance. It exports trichodermin, but it is not the only exporter of this secondary metabolite (Liu et al. 2012). Trichothecenes are the sesquiterpenes secreted by Trichoderma spp. residing in the rhizosphere.
These compounds have been reported to act as plant growth promoters and bio-control agents (Chaudhary et al. 2016).

The PfMFS transporter (551 aas; 14 putative TMSs) is involved in the acid resistance and intracellular pH homeostasis of Penicillium funiculosum (Xu et al. 2014). This protein was not in UniProt, and its closest orthologue, PmMFS of Penicillium marneffei, is therefore presented here.

2-phosphonoacetate/2-phosponopropionate uptake porter of 428 aas, PhnB. The PhnA protein is a hydrolase, and PhnC is a positive transcriptional regulator. Induction occurs with either of the two substrates (Kulakova et al. 2001).

β- and α-galactopyranoside:H+ symporter, LacY. Transports
lactose, melibiose, thio-β-methyl galactopyranoside (TMG), isopropyl-β-thiogalactoside (IPTG), 4-nitrophenyl-beta-D-galactopyranoside, 4-nitrophenyl-alpha-D-galactopyranoside and galactopyranosyl-1-glycerol. Single point mutations allow transport of sucrose and maltose (King and Wilson 1990). Crystal structures and modeling reveal the
cytoplasmic open state and the periplasmic open state (PDB ID: 1PV7). A structure with a bound lactose homolog, beta-D-galactopyranosyl-1-thio-beta-D-galactopyranoside, revealed the sugar-binding site in a cavity, and residues that play major roles in substrate recognition and proton translocation were identified (Abramson et al., 2003; Pendse et al., 2010). The
membrane lipid composition determines the topology of LacY (Dowhan and
Bogdanov, 2011). Smirnova et al. (2011) have
provided evidence that the opening of the periplasmic cavity in LacY is the
limiting step for sugar binding. Evidence for an alternating sites mechanism of
transport has been summarized (Smirnova et al., 2011). Eames
and Kortemme (2012) have shown that when
considering expression of the lac operon, LacY function (H+ co-transport)
and not protein production is the primary origin of cost fitness. Homology
threading of several MFS porters based on the LacY 3-d structure has been
reported (Kasho et al., 2006). The
alternating-access mechanism has been suggested to arise from inverted
topological repeats (Radestock and Forrest, 2011; Madej et al. 2012), but
this proposal has been contested (Västermark and Saier 2014; Västermark et al. 2014).
Mechanistic features of LacY have been summarized (Kaback 2015). Insertion into the membrane depends on YidC (TC# 2.A.9.3.1) and may occur in a stepwise, stochastic manner employing multiple coexisting pathways to complete the folding process (Serdiuk et al. 2017). The glucose Enzyme IIA (Crr) protein binds LacY to allosterically inhibit its activity, promoting inducer exclusion (Hoischen et al. 1996; Hariharan et al. 2015). Protonated LacY binds D-galactopyranosides specifically, inducing an
occluded state that can open to either side of the membrane (Kumar et al. 2014). LacY can form amyloid-like fibrils under destabilizing conditions (Stroobants et al. 2017). Multiple conformations of LacY have been solved (Kumar et al. 2018).

Sucrose:H+ symporter, CscB, also transports maltose (Peng et al. 2009). CscB recognizes not just sucrose but also fructose and lactulose, but
glucopyranosides are not transported and do not inhibit sucrose
transport (Sugihara et al. 2011).

The melibiose uptake porter of 425 aas and 12 TMSs. Takes up lactose and melibiose, but in contrast to LacY of E. coli, it binds, but does not transport thiomethyl-β-galactoside,TMG (Tavoulari and Frillingos 2008).

Uncharacterized protein of 894 aas and 19 TMSs in a 7 + 12 TMS arrangement. The first 7 TMSs comprise a CFEM domain, while the last 12 TMSs are homologous to MFS porters. There are many such proteins in the NCBI database, most from fungi.

Nitrate/H+ symporter (K1);Nitrate/nitrite antiporter (K2). The 3-d structure is available revealing a positively charged pathway for nitrate/nitrite lined with arginine residues with no apparent proton pathway suggesting exchange transport is the primary or sole mechanism. The pathway is between the two halves of the protein and a rocker switch mechanism was proposed (Zheng et al. 2013). In an in vitro reconstituted system, NarK appeared to be a nitrate/nitrite
antiporter. High-resolution
crystal structures in the nitrate-bound occluded, nitrate-bound
inward-open and apo inward-open states have been solved (Fukuda et al. 2015).

The 24 TMS, 2 domain, NarK1-NarK2 porter (NarK1 = a NO3-/H+ symporter; NarK2 = a NO3-/NO2- antiporter). NarK1 is a nitrate/proton symporter with high affinity for nitrate while NarK2 is a nitrate/nitrite antiporter with lower affinity for nitrate (Goddard et al., 2008). Each transporter requires two conserved arginine residues for activity. A transporter consisting of inactivated NarK1 fused to active NarK2 has a dramatically increased affinity for nitrate compared with NarK2 alone, implying a functional interaction between the two domains (Goddard et al., 2008).

The root cortical and epidermal cell, high affinity, plasma membrane, NO3- uptake transporter, NRT2.1 (Wirth et al., 2007). Also functions in nitrate sensing and signaling (Miller et al., 2007; Girin et al., 2010). Activity only occurs when NRT2.1 is complexed with NAR2.1 (WR3; 8.A.20.1.1) in a 2:2 tetrameric complex (Yong et al., 2010). NAR2.1 has an N-terminal and a C-terminal TMS and has been annotated as a calcineurin-like phosphoesterase family member (Yong et al., 2010). Ntr transporters may also play a role in gaseous NO2 uptake by leaves (Hu et al. 2014). The Medicago truncatula orthologue has been characterized (Pellizzaro et al. 2014).

Nitrate/nitrite transporter, NarK2, of 468 aas and 12 TMSs. The narK1 and narK2 genes are located in an operon, narK1K2GHJI, with the structural genes for the nitrate reductase complex. Utilizing an isogenic narK1 mutant, a narK2 mutant, and a narK1K2 double mutant, Sharma et al. 2006 explored the effect on growth under denitrifying conditions. While the ΔnarK1::Gm mutant was only slightly affected, but both the ΔnarK2::Gm and double mutants exhibited poor nitrate-dependent, anaerobic growth although all three strains had wild-type levels of nitrate reductase activity. Nitrate uptake measurements showed that NarK2 has most of the activity. E. coli narK rescued both mutants.

Phosphate transporter, PT, of 543 aas and 12 TMSs. It has a micormolar Km for phosphate uptake, is found in the plasma membrane and is induced by low medium phosphate concentrations (Wang et al. 2014).

Phosphate transporter and receptor (transceptor) of 543 aas and 12 TMSs. Important for signalling and uptake of phosphate. The majority of terrestrial vascular plants can form mutualistic associations with
obligate biotrophic arbuscular mycorrhizal (AM) fungi from the phylum Glomeromycota. This
mutualistic symbiosis provides carbohydrates to the fungus, and reciprocally improves plant
phosphate uptake. AM fungal transporters can acquire phosphate from the soil through the hyphal
networks. Xie et al. 2016 reported a high-affinity phosphate transporter GigmPT that is required for AM
symbiosis. GigmPT functions as a phosphate transceptor for
the activation of the phosphate signaling pathway as well as the protein kinase A signaling cascade.

Xanthosine porter, XapB. Xanthosine, inosine, adenosine, cytidine and thymidine but not guanosine and uridine are transported (Seeger et al. 1995). The Km for Xanthosine is 136 μM (Nørholm and Dandanell 2001). The transporter is encoded within an operon with xanthosine phosphorylase which is inactive in S. enterica but can be mutated to the active form (Hansen et al. 2006).

The sialic acid porter, NanT. N-acetylneuraminic acid (Neu5Ac) serves as a sole source of carbon and
nitrogen for E. coli. It is a mucus-derived carbon source in the
mammalian gut. NanT can also take up and allow efficient growth on the related sialic acids,
N-glycolylneuraminic acid (Neu5Gc) and
3-keto-3-deoxy-d-glycero-d-galactonononic acid (KDN) (Hopkins et al. 2013).

The lactate/pyruvate:H+ symporter. Residues in the substrate translocation pathway have been reported (Soares-Silva et al., 2011). This systems and its orthologs in fungi have been reviewed (Guo et al. 2018).

MCTs play roles in the absorption, tissue distribution, and
clearance of both endogenous and exogenous compounds. MCTs are required
for the transport of essential cell nutrients and for cellular metabolic and pH regulation (Jones and Morris 2016).

Solute carrier family 16, member 5 (monocarboxylic acid transporter 6) of 505 aas and 12 TMSs. Found on the luminal side of small intestinal epithelial cells (Kohyama et al. 2013).
MCT6 mediates uptake of nateglinide, an oral hypoglycemic agent. The K(t) for
nateglinide is 46 μM. Thus, MCT6 may play a role in the intestinal absorption
of nateglinide, although other transporters are also likely to be involved (Kohyama et al. 2013).

Lysosomal sialate transporter (Salla disease and infantile sialate storage disease protein (Morin et al., 2004)). Also transports glucuronic acid and aspartate. Structure-function studies have identify crucial residues and substrate-induced conformational changes (Courville et al., 2010). Also called SLC17A5. The substrate binding pocket has been identified based on modeling studies (Pietrancosta et al., 2012). NAAG (N-acetylaspartylglutamate) an abundant neuropeptide in the
vertebrate nervous system that is released from synaptic terminals in a
calcium-dependent manner and acts as an agonist at the
type II metabotropic glutamate receptor mGluR3, is transported into synaptic vesicles
before it is secreted. Lodder-Gadaczek et al. 2013 demonstrate that vesicular uptake
of NAAG and the related peptide NAAG2
(N-acetylaspartylglutamylglutamate) is mediated by sialin (SLC17A5). Sialin is probably the only vesicular
transporter for NAAG and NAAG2, because transport of both peptides was not detectable in vesicles isolated from sialin-deficient mice. Sialin also transports nitrate in the plasma membrane of salivary glands (Qin et al. 2012).

MhpT. A specific 3-(3-hydroxyphenyl)propionate (3HPP) transporter; vital for E. coli K-12 W3110 to grow on this substrate. Transports 3HPP but not benzoate, 3-hydroxybenzoate or gentisate (Xu et al. 2013). May also export arabinose but not xylose (Koita and Rao 2012).

2.A.1.19: The Organic Cation Transporter (OCT) Family (The SLC22A family including OCT1-3, OCTN1-3 and OAT1-5 of H. sapiens)

This family has been described by Koepsell 2013. It contains 13 functionally characterized human plasma membrane proteins.The family includes organic cation transporters
(OCTs), organic zwitterion/cation transporters (OCTNs), and organic anion transporters (OATs). The
transporters operate as (1) uniporters which mediate facilitated diffusion (OCTs and some OCTNs), (2) anion
exchangers (OATs), and (3) some Na+/zwitterion cotransporters (OCTNs). They participate in small
intestinal absorption and hepatic and renal excretion of drugs, xenobiotics and endogenous compounds
and perform homeostatic functions in the brain and heart. Important endogeneous substrates include
monoamine neurotransmitters, l-carnitine, alpha-ketoglutarate, cAMP, cGMP, prostaglandins and
urate. Mutations in the SLC22 genes cause
specific diseases like primary systemic carnitine deficiency and idiopathic renal hypouricemia and
are correlated with diseases such as Crohn's disease and gout. Drug-drug interactions at individual
transporters may change pharmacokinetics and toxicities of drugs (Koepsell 2013). Models of Octs resemble GLUT3 (PDB ID# 5C65) and have an intracellular three/four-helix loop between TMH6 and TMH7 containing putative phosphorylation sites for precise regulation of hOCTs. The models allow prediction of substrate binding sites (Dakal et al. 2017). Interactions with therapeutic herbal products, dietary supplements, and clinically important drugs are discussed, and the significance of these transporters in modulating the severity of drug-related side effects and toxicity mechanisms have been reviewed (Mor et al. 2018).

It is also the cell surface receptor for Lipocalin-2 (LCN2; 24p3) that plays a key role in iron
homeostasis and transport. Able to bind iron-bound LCN2,
followed by internalization and release of iron, thereby
increasing intracellular iron concentration and leading to inhibition of
apoptosis. Also binds iron-free LCN2, followed by
internalization and its association with an intracellular
siderophore, leading to iron chelation and iron transfer to the
extracellular medium, thereby reducing intracellular iron concentration
and resulting in apoptosis.

The high affinity L-carnitine transporter, CT2, present in the luminal membranes of epididymal epithelia and Sertoli cells of the testis (Enomoto et al., 2002b). It also catalyzes uptake of the anticancer polyamine analogue, bleomycin-A5 (Aouida et al. 2010). Carnitine uptake and metabolism have been reviewed (Nałęcz and Nałęcz 2017).

solute carrier family 22, member 14, Slc22a14, is crucial for sperm motility and male fertility in mice. It is expressed
specifically in male germ cells, and mice lacking the Slc22a14 gene show severe male infertility as well as sperm morphological changes (Maruyama et al. 2016).

The macrolide (erythromycin; oleandomycin; azithromycin; telithromycin) efflux pump, MefA, of 405 aas and 12 TMSs (Cantón et al. 2005; Bley et al. 2011). Iannelli et al. 2018 suggested that MefA can function with an ATPase, MsrD (TC# 3.A.1.121.6), and therefore function as an ABC drug exporter. However, the data presented seem inconsistent with this suggestion. The two genes encoding these two proteins are adjacent to each other, suggesting that they may function together (Iannelli et al. 2018).

Macrolide efflux pump, MefE (Mef; MefA) of 405 aas. Induced by erythromycin and the antimicrobial peptide, LL-37 (Zähner et al. 2010). May act in conjunction with Mel (Q93QE4), an ABC-type ATPase that is encoded in the same operon with the mefA gene (Ambrose et al. 2005).

Bacillibactin exporter, YmfE (199aas; 6TMSs) (Miethke et al., 2008) (resembles the 2nd half of YitG of B. subtilis (2.A.1.32.1). The sequence provided under acc# O31763 is only a fragment of the full length gene.

MFS homologue, YqgE. It is cotranscribed with ftsI, encoding the peptidoglycan transpeptidase that crosslinks peptidoglycan strands, releasing free D-alanine. Possibly YqgE is a D-alanine uptake porter. Its expression causes a decrease in the amount of sigma W synthesis, the sigma factor for genes involved in detoxification and antimicrobial synthesis (Turner and Helmann 2000).

The lysophospholipid (LPL) transporter, LplT (Harvat et al., 2005). Substrates include lyso-PE, lyso-cardiolipin, diacylcardiolipin, fully-deacylated cardiolipin and lyso-phosphatidylglycerol, but not lysophosphatidylcholine, lysophosphatidic acid or phosphatidic acid (Lin et al. 2016). Reacylation by acyltransferase/acyl-acyl
carrier protein synthetase then occurs on the inner leaflet of the membrane.Thus, a fatty acid chain is not required for LplT
transport. A "sideways sliding"
mechanism was proposed to explain how a conserved membrane-embedded α-helical
interface excludes diacylphospholipids from the LplT binding site to
facilitate efficient flipping of lysophospho-lipids across the cell
membrane (Lin et al. 2016). Thus, a fatty acid chain is not required for LplT
transport. Fruther, LplT cannot transport lysophosphatidic acid,
and its substrate binding was not inhibited by either orthophosphate or
glycerol 3-phosphate, indicating that either a glycerol or ethanolamine
headgroup is the chemical determinant for substrate recognition. Diacyl
forms of PE, phosphatidylglycerol, or the tetra-acylated form of
cardiolipin could not serve as competitive inhibitors .A "sideways sliding"
mechanism was proposed to explain how a conserved membrane-embedded α-helical
interface can exclude diacylphospholipids from the LplT binding site. A dual substrate-accessing mechanism, in which LplT recruits LPLs to its substrate-binding site via two routes, either from its extracellular entry site, or through a membrane-embedded groove between transmembrane helices, and it then moves them towards the inner membrane leaflet (Lin et al. 2018).

The magnetosome permease fused to a C-terminal YedZ-like domain, MamZ (von Rozycki et al., 2004). This protein has 649 aas and 18 TMSs with a C-terminal YedZ domain and is therefore in the YedZ superfamily as well as the MFS. The two MFS proteins in the magnetosome membrane, MamZ and MamH (44% identical to MamZ), appear to overlap in function as deletion of their two genes have additive effects (Raschdorf et al. 2013). Magnetosome biogenesis has been reviewed ().

L-amino acid transporter-4 (LAT4) has the same specificity and is 57% identity to LAT3. Na+, Cl- and pH independent; not trans-stimulated; two kinetic components, a low affinity component sensitive to NEM, and a high affinity component insensitive to NEM. Found in the basolateral membrane of epithelial cells in the distal tubule and collecting duct of the kidney and the crypt cells in the intestine (Bodoy et al., 2005).

Originally considered to be vacuolar basic amino acid transporter 4, but it my not act on amino acids, but exports drugs such as azoles. May also play a role in vacuolar morphology (Kawano-Kawada et al. 2015).

Multidrug efflux transporter, MET, of 507 aas and 12 TMSs (Chahine et al. 2012). Exposure to dietary methotrexate was associated with increased fluid
secretion rate and increased flux of methotrexate, but not salicylate.
Exposure to methotrexate in the diet resulted in increases in the
expression of a multidrugeffluxtransporter gene (MET; CG30344) in the Malpighian tubules. There were also increases in expression of genes for either a Drosophila multidrug resistance-associated protein (dMRP; CG6214; TC# 3.A.1.208.39) or an organic anion
transporting polypeptide (OATP; CG3380; TC# 2.A.60.1.27), depending on the concentration
of methotrexate in the diet. MET probably does not export methotrexate (Chahine et al. 2012).

MFS uptake permease specific for pyrimidines, PhtC of 422 aas and 12 TMSs. Together with PhtD (TC# 2.A.1.53.6), it contributes to protection of L. pneumophila from dTMP starvation, protects the cell from 5-fluorodeoxyuridine (FUdR) toxicity and is required for growth of L. pneumophila in macrophage (Fonseca et al. 2014).

MFS uptake permease, probably specific for pyrimidines, PhtD of 427 aas and 12
TMSs. Together with PhtC (TC# 2.A.1.53.6), it contributes to
protection of L. pneumophila from dTMP starvatioin, protects the cell from 5-fluorodeoxyuridine (FUdR) toxicity and is required for growth of L. pneumophila in macrophage (Fonseca et al. 2014).

The Ferripyochelin uptake permease, FptX (Michel et al., 2007). Also transports N-acetylglucosamine anhydrous N-acetylmuramyl peptides and is called AmpP or AmpGh1 (Kong et al. 2010). However, it does not play a role in the induction of β-lactam resistance (Zhang et al. 2010).

May contribute to coordination of muscle contraction as regulatory subunit of a nonessential potassium channel complex. Subunit structure: May form a complex with sup-9 and sup-10 where unc-93 and sup-10 act as regulatory subunits of the two pore potassium channel sup-9.

Unc-93b1 or Unc93b1 of 597 aas and 12 TMSs. Plays
a role in innate and adaptive immunity by regulating
nucleotide-sensing Toll-like receptor (TLR) signaling. Required for the
transport of a subset of TLRs (including TLR3, TLR7 and TLR9) from the
endoplasmic reticulum to endolysosomes where they can engage pathogen
nucleotides and activate signaling cascades. May play a role in
autoreactive B-cells removal (Isnardi et al. 2008). Induces apoptotic cell death and is cleaved by host and viral proteases (Harris and Coyne 2015).

MFS permease of unknown function (First half resembles 2.A.1.3.7 (e-11) and 2.A.1.15.3 (e-8)). Very likely to be a galactoside/galactose transporter; encoded within a gene cluster with β-galactosidase and galactose metabolic genes.

ArsK, exporter of arsenite, antimonite, trivalent roxarsone and methylarsenite (Shi et al. 2018). Expression of arsK is induced by arsenite [As(III)], antimonite
[Sb(III)], trivalent roxarsone [Rox(III)], methylarsenite [MAs(III)] and
arsenate [As(V)], and heterologous expression of ArsK in an
arsenic-hypersensitive E. coli strain showed that ArsK is
essential for resistance to As(III), Sb(III), Rox(III) and MAs(III) but
not to As(V), dimethylarsenite [Dimethyl-As(III)] or Cd(II). ArsK
reduces the cellular accumulation of As(III), Sb(III), Rox(III) and
MAs(III) but not to As(V) or Dimethyl-As(III). An arsenic
regulator gene arsR2 is cotranscribed with arsK, and ArsR2 interacts with the arsR2-arsK promoter region without metalloids but is derepressed by As(III),
Sb(III), Rox(III) and MAs(III). Thus, ArsK is an arsenic efflux protein and is regulated by ArsR2 (Shi et al. 2018).

Probable transporter MCH1. Although the name, "monocarboxylate transporter homologue 1" implies that this system transports monocarboxylates such as lactate, pyruvate and acetate, no evidence for this possibility was obtained (Makuc et al. 2001). Instead, the mch1-5 mutant strain, lacking all 5 such paralogues in yeast showed strongly reduced biomass yields in aerobic
glucose-limited chemostat cultures, pointing to the involvement of Mch
transporters in mitochondrial metabolism. Indeed, intracellular
localization studies indicated that at least some of the Mch proteins
reside in intracellular membranes.Thus, the yeast monocarboxylate transporter-homologs perform other functions other than do their mammalian counterparts (Makuc et al. 2001). Possibly they function in intracellular, organellar transport of these acids.

Synaptic vesicle 2-related protein (SV2-related protein), SVOP. This protein localizes to neurotransmitter-containing vesicles and has a nucleotide binding site (Yao and Bajjalieh 2009). ATP, GTP and NAD show binding affinities with the highest affinity for NAD, in contrast to SV2 (TC# 2.A.1.22.1), which binds both
NAD and ATP with equal affinity.

MFS porter; 1-arseno-3-phosphoglycerate (1As3PGA) exporter, ArsJ. Encoded in an operon concerned with arsenic resistance, encoding the enzymes and transporters of a new pathway of arsenic biotransformation. The adjacent gene encodes a 3-phosphoglycerate dehydrogenase homologue that probably forms the substrate of this MFS porter which could be expelled from the cell (Chen et al. 2016).

MFS uptake permease. The gene is adjacent to a putative SAM-dependent methyl transferase, one homologue of which is a puromycin methyl transferase. Perhaps the transport substrate is a drug that is modified by methylation for detoxification purposes. This family is most closely, but distantly related to the AAHS family (2.A.1.15).